5'-Methylthioadenosine (MTA) is enzymatically synthesized by at least five separate pathways including polyamine biosynthesis. Although the cellular functions of MTA are unknown, recent reports indicate that exogenous MTA can dramatically inhibit cellular biosynthetic processes. Of particular interest are our recent findings which demonstrate the inhibitory effects of exogenous MTA on DNA and protein synthesis in activated lymphocytes. The overall objectives of this proposal are: a) to study the mechanisms by which MTA can inhibit cell activation, and b) to determine the usefulness of MTA as a regulator of the immune response and neoplastic cell growth. Specific objectives to be completed include: a) Determining the effect of MTA on lymphocytes activated by mitogens and antigens, on proliferating tumor cell lines in vivo and in vitro, and on the primary and secondary immune response in guinea pigs and rabbits. b) Monitoring levels of MTA, its precursors and its breakdown products in quiescent and actively metabolizing lymphoid and tumor tissue. c) Monitoring the activity of the enzymes involved in MTA biosynthesis and degradation in quiescent and activated tissues. d) Describing the effects of MTA and its analogues on activated cells, MTA metabolism, and on graft rejection, autoimmunity and tumor immunity. The production and degradation of MTA in activated cells, coupled with its known inhibitory effects on macromolecule biosynthesis, implicate MTA as having important regulatory potential. Understanding the regulatory mechanisms involving MTA may lead to a more effective control of neoplastic cell growth and immune responsiveness.